Lipids & metabolic liver disease
Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study
Authors' conclusion
Our findings support the suggestion that glucagon receptor signalling is involved in MASLD, that plasma levels of proglucagon are linked to the risk of type 2 diabetes development, and that proglucagon levels are influenced by genetic variation in the glucagon receptor, obesity, type 2 diabetes and MASLD. Determining the molecular signalling pathways downstream of glucagon receptor activation may guide the development of biased GLP-1/glucagon co-agonist with improved metabolic benefits.
Study context
- Population
- ≈410,000 white UK Biobank participants with exome sequencing data; plasma proglucagon (Olink) available for a subset (≈40,000)proglucagon in ≈40,000
- Participants
- ≈410,000 participants
- Exposure
- Glucagon receptor variant carriers vs wild-type; baseline proglucagon levels and T2D risk
- Outcome
- Determinants of plasma proglucagon and associations with metabolic disease
Methodological detailsUK Biobank, exome sequencing, survival analyses
- UK Biobank
- Exome sequencing
- Survival analyses
Main finding
As reported in the abstract
Baseline proglucagon and risk of T2D development over 14 years (n=1562; p=1.3×10-12)
HR 1.13; 95% CI 1.09, 1.17
Carriers of glucagon receptor variants with reduced cAMP signalling: elevated proglucagon (n=17; p=0.04)
β 0.847; 95% CI 0.04, 1.66
Carriers of predicted frameshift variants: higher liver fat vs wild-type reference (n=11; p=0.04)
β 0.504; 95% CI 0.03, 0.98
Observational data: associations, not effects.
Original publication
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